Soluble tumor necrosis factor receptor treatment of medical disorders

ABSTRACT

The invention pertains to methods and compositions for treating medical disorders characterized by elevated levels or abnormal expression of TNFα by administering a TNFα antagonist, such as recombinant TNFR:Fc.

This application is a divisional of U.S. application Ser. No.13/021,545, filed Feb. 4, 2011, now allowed; which is a continuation ofU.S. application Ser. No. 12/394,962, filed Feb. 27, 2009, now U.S. Pat.No. 7,915,225; which is a divisional of U.S. application Ser. No.10/853,479, filed May 25, 2004, now abandoned; which is a divisional ofU.S. application Ser. No. 09/602,351, filed Jun. 23, 2000, nowabandoned, which claims benefit of U.S. Provisional Application Nos.60/164,676, filed Nov. 10, 1999, now abandoned, and 60/184,864, filedFeb. 25, 2000, now abandoned; and which is a continuation-in-part ofU.S. application Ser. No. 09/373,828, filed Aug. 13, 1999, nowabandoned, which claims the benefit of U.S. Provisional Application Nos.60/130,074, filed Apr. 19, 1999, now abandoned, 60/134,320, filed May14, 1999, now abandoned, 60/143,959, filed Jul. 15, 1999, now abandoned,and 60/148,234, filed Aug. 11, 1999, now abandoned; all of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention pertains to methods for treating various medical disordersthat are characterized by abnormal or excessive TNFα levels byadministering a TNFα antagonist, preferably a soluble TNFα. The TNFαinhibitor may be administered in combination with other biologicallyactive molecules.

BACKGROUND OF THE INVENTION

The pleiotropic cytokine tumor necrosis factor alpha (TNFα) isassociated with inflammation and binds to cells through membranereceptor molecules, including two molecules having molecular weights ofapproximately 55 kDa and 75 kDa (p55 and p75). In addition to bindingTNFα, the p55 and p75 TNF receptors mediate the binding to cells ofhomotrimers of TNFβ, which is another cytokine associated withinflammation and which shares structural similarities with TNFα (e.g.,see Cosman, Blood Cell Biochem 7:51-77, 1996). TNFβ is also known aslymphotoxin-α (LTα).

It has been proposed that a systemic or localized excess of TNFαcontributes to the progression of numerous medical disorders. Forexample, patients with chronic heart failure have elevated levels ofserum TNFα, which have been shown to increase with disease progression(see, for example, Levine et al., N Eng J Med 323:236-241, 1990). Avariety of other diseases are associated with elevated levels of TNFα(see, for example, Feldman et al., Transplantation Proceedings30:4126-4127, 1998).

Psoriatic arthritis (PsA) is a chronic autoimmune condition that sharessome features with both rheumatoid arthritis (RA) and the inflammatoryskin disease psoriasis (for review, see Breathnach, In Klippel andDieppe eds. Rheumatology, 2^(nd) Ed., Mosby, 1998, 22.1-22.4). Psoriasisis characterized by epidermal keratinocyte hyperproliferation,accompanied by neutrophil and T cell infiltration, and is associatedwith elevated levels of inflammatory cytokines, including TNFα, IL-6 andTGFβ (see, for example, Bonifati et al., Clin Exp Dermatol 19:383-387,1994). Psoriasis and PsA are different clinical entities, and areassociated with somewhat different MHC haplotypes (Gladman, Rheum DisClin NA. 18:247-256, 1992; Breathnach, 1998). The overall prognosis forPsA is far worse than for ordinary psoriasis. Nonetheless, treatmentsused for the psoriatic lesions of PsA generally are similar to thoseused to treat psoriasis.

Psoriatic skin lesions are present in patients with PsA, although only aminority of psoriasis sufferers actually have PsA. Ordinary psoriasisoccasionally is accompanied by joint pain, but does not involve theextreme pain and often deforming degeneration of joints and bone thatoccurs in PsA patients.

Treatments that sometimes are effective in treating ordinary psoriasisinclude topical medications (e.g., steroids, coal tar, anthralin, DeadSea salts, various natural oils, vitamin D3 and its analogs, sunshine,topical retinoids), phototherapy (e.g., ultraviolet light,photochemotherapy (PUVA)), and internal medications (e.g., methotrexate,systemic steroids, oral retinoids, cyclosporine, or a rotating regimenof these three). In addition, it has been proposed that psoriasis couldbe treated with TNF-derived peptides, quinolinesulfonamides,pyrrolidinone derivatives, catechol diether compounds, isoxazolinecompounds, matrix metalloproteinase inhibitors or mercapto alkylpeptidyl compounds, all of which inhibit either TNFα production or itsrelease from cultured cells (see, for example, U.S. Pat. No. 5,691,382,U.S. Pat. No. 5,834,485, U.S. Pat. No. 5,420,154, U.S. Pat. No.5,563,143, U.S. Pat. No. 5,869,511 and U.S. Pat. No. 5,872,146), as wellas with various combination therapies involving TNFα antagonists (forexample, see U.S. Pat. No. 5,888,511 or U.S. Pat. No. 5,958,413).

Conflicting results have been reported regarding the role of TNFα inpsoriasis. Some investigators have proposed that overproduction of TNFαcontributes to the pathology of psoriasis (e.g., Pigatto et al., JInvest Dermatol 94:372-376, 1990; Sagawa et al., Dermatol 187:81-83,1993; Ameglio et al., Dermatol 189:359-363, 1994). One group reportedsome improvement after treatment with pentoxifylline, a drug that caninhibit the release of TNFα, but which exerts many of its physiologicaleffects by inhibiting cyclic AMP phosphodiesterase (Omulecki et al., JAm Acad Dermatol 34:714-715, 1996; Centola et al., J Androl 16:136-142,1995; Elferinck et al., Biochem Pharmacol 54:475-480, 1997). However,other reports have cast doubt on the hypothesis that overproduction ofTNFα exacerbates psoriasis. For example, some investigators havereported that treatment with TNFα itself actually can mitigate psoriasis(see, e.g., Takematsu et al., Br J Dermatol 124:209-210, 1991; Creavenet al., J Am Acad Dermatol 24:735-737, 1991).

In addition to psoriatic lesions, PsA is characterized by distalinterphalangeal joint (DIP) involvement, enthesopathy, nail lesions,spondylitis and dactylitis. The histopathogenesis of PsA and the morewell-studied rheumatoid arthritis share certain features. In both RA andin active PsA, patients exhibit increased levels of HLA-DR⁺ T cells andMHC class II antigens in their synovial membranes and synovial fluid, aswell as increased expression of the cytokine TNFα. In addition, bothdiseases are associated with prominent synovial vascular changes.

The discovery of rheumatoid factor in the serum of RA patients providedan important tool for differentiating PsA from RA, but the realizationthat RA and PsA are distinct diseases was based primarily on their manyclinical differences (e.g., Helliwell and Wright, In Klippel and Dieppeeds. Rheumatology, 2^(nd) Ed., Mosby, 1998, 21.1-21.8). Studies haveshown that levels of TNFα, Il-1β, Il-8 as well as TNFα receptors insynovial fluids were higher in PsA patients than in osteoarthritispatients, though they were lower than in RA patients (Partsch et al., JRheumatol 24:518-523, 1997; Partsch et al., J Rheumatol 25:105-110,1998; Partsch et al., Ann Rheum Dis 57:691-693, 1998). PsA isdistinguished from RA also by radiographic appearance, a notably higherdegree of synovial membrane vascularity as well as differences in thelevels of various cytokines in the synovial fluids (Ritchlin et al., JRheumatol 25:1544-52, 1998; Veale et al., Arth Rheum 36:893-900, 1993).Veale et al. noted differences in synovial membrane adhesion moleculesand numbers of macrophages when they compared RA and PsA patients, aswell as observing a minimal degree of hyperplasia and hypertrophy ofsynoviocytes in PsA as compared with RA patients. Because of suchdifferences, coupled with the association of PsA but not RA with class IMHC antigens, Ritchlin et al. have suggested that PsA must be triggeredby different mechanisms than those underlying RA. Veale et al. suggestedfor similar reasons that different cytokines were likely to beinteracting in the synovium of PsA and RA patients.

Most of the drugs used for treating the arthritic aspects of PsA aresimilar to those used in RA (Salvarini et al., Curr Opin Rheumatol10:229-305, 1998), for example the non-steroidal antiinflammatories(NSAIDs), which may be used alone or in combination with thedisease-modifying anti-rheumatic drugs, or “DMARDs.” However, one groupfound that long-term administration of the DMARD methotrexate failed toslow the progression of joint damage in PsA patients (Abu-Shakra et al.,J Rheumatol 22:241-45, 1995), and another group reported very littleimprovement in PsA patients who had received methotrexate (Willkens etal., Arthr Rheum 27:376-381, 1984). Similarly, Clegg et al. found only aslight improvement over placebo in PsA patients treated withsulfasalazine, another drug classified as a DMARD (Clegg et al.,Arthritis Rheum 39: 2013-20, 1996). Some studies have indicated that theimmunosuppressor cyclosporine is effective in treating PsA (reviewed inSalvarini et al., 1998), though this drug has severe side effects. Inaddition, others have proposed that PsA could be treated with truncatedTNFα receptors or with a combination of methotrexate and antibodiesagainst TNFα (WO 98/01555; WO 98/0537).

A recent meta-analysis of a number of PsA treatment studies concludedthat PsA and RA differed not only in their response to treatment withspecific drugs, but in the relative magnitudes of improvement in theplacebo arms of the studies (Jones et al., Br J Rheumatol 36:95-99,1997). As an example, PsA patients responded better to gold salt therapythan did RA patients, though the gold did not affect the psoriatic skinlesions (Dorwart et al., Arthritis Rheum 21:515-513, 1978).

It has been suggested that the suppression of TNFα might be beneficialin patients suffering from various disorders characterized by abnormalor excessive TNFα expression. However, although progress has been madein devising effective treatment for such diseases, improved medicamentsand methods of treatment are needed.

SUMMARY OF THE INVENTION

Provided herein are methods for treating a number of medical disorderscharacterized by abnormal TNFα expression by repeatedly administering anantagonist of TNFα, such as a soluble TNFα receptor, for a period oftime sufficient to induce a sustained improvement in the patient'scondition.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides compounds, compositions and methods for treatinga mammalian patient, including a human patient, who is suffering from amedical disorder that is characterized by abnormal or elevatedexpression of TNFα. For purposes of this disclosure, the terms“illness,” “disease,” “medical condition,” “abnormal condition” and thelike are used interchangeably with the term “medical disorder.”

The subject methods involve administering to the patient a soluble TNFαantagonist that is capable of reducing the effective amount ofendogenous biologically active TNFα, such as by reducing the amount ofTNFα produced, or by preventing the binding of TNFα to its cell surfacereceptor (TNFR). Antagonists capable of inhibiting this binding includereceptor-binding peptide fragments of TNFα, antibodies directed againstTNFα, and recombinant proteins comprising all or portions of receptorsfor TNFα or modified variants thereof, including genetically-modifiedmuteins, multimeric forms and sustained-release formulations. Othercompounds suitable for treating the diseases described herein includethalidomide and pentoxifylline.

Preferred embodiments of the invention utilize soluble TNFRs as the TNFαantagonist. Soluble forms of TNFRs may include monomers, fusion proteins(also called “chimeric proteins), dimers, trimers or higher ordermultimers. In certain embodiments of the invention, the soluble TNFRderivative is one that mimics the 75 kDa TNFR or the 55 kDa TNFR andthat binds to TNFα in the patient's body. The soluble TNFR mimics of thepresent invention may be derived from TNFRs p55 or p75 or fragmentsthereof. TNFRs other than p55 and p75 also are useful for derivingsoluble compounds for treating the various medical disorders describedherein, such for example the TNFR described in WO 99/04001. Soluble TNFRmolecules used to construct TNFR mimics include, for example, analogs orfragments of native TNFRs having at least 20 amino acids, that lack thetransmembrane region of the native TNFR, and that are capable of bindingTNFα. Antagonists derived from TNFRs compete for TNFα with the receptorson the cell surface, thus inhibiting TNFα from binding to cells, therebypreventing it from manifesting its biological activities. Binding ofsoluble TNFRs to TNFα or LTα can be assayed using ELISA or any otherconvenient assay. This invention provides for the use of soluble TNFαreceptors in the manufacture of medicaments for the treatment ofnumerous diseases.

The soluble TNFR polypeptides or fragments of the invention may be fusedwith a second polypeptide to form a chimeric protein. The secondpolypeptide may promote the spontaneous formation by the chimericprotein of a dimer, trimer or higher order muimer that is capable ofbinding a TNFα and/or LTα molecule and preventing it from binding tocell-bound receptors. Chimeric proteins used as antagonists include, forexample, molecules derived from an antibody molecule and a TNFR. Suchmolecules are referred to herein as TNFR-Ig fusion proteins. A preferredTNFR-Ig fusion protein suitable for treating diseases in humans andother mammals is recombinant TNFR:Fc, a term which as used herein refersto “etanercept,” which is a dimer of two molecules of the extracellularportion of the p75 TNFα receptor, each molecule consisting of a 235amino acid TNFR-derived polypeptide that is fused to a 232 amino acid Fcportion of human IgG₁. Etanercept is currently sold by ImmunexCorporation under the trade name ENBREL.® Because the p75 receptorprotein that it incorporates binds not only to TNFα, but also to theinflammatory cytokine LTα, etanercept can act as a competitive inhibitornot only of TNFα, but also of LTα. This is in contrast to antibodiesdirected against TNFα, which cannot inhibit LTα. Also encompassed by theinvention are treatments using a compound that comprises theextracellular portion of the 55 kDa TNFR fused to the Fc portion of IgG,as well as compositions and combinations containing such a molecule.Encompassed also are therapeutic methods involving the administration ofTNFR-Ig proteins derived the extracellular regions of TNFα receptormolecules other than the p55 and p75 TNFRs, such as for example the TNFRdescribed in WO 99/04001.

In one preferred embodiment of the invention, sustained-release forms ofsoluble TNFRs are used, including sustained-release forms of TNFR:Fc.Sustained-release forms suitable for use in the disclosed methodsinclude, but are not limited to, TNFRs that are encapsulated in aslowly-dissolving biocompatible polymer (such as the alginatemicroparticles described in U.S. Pat. No. 6,036,978), admixed with sucha polymer (including topically applied hydrogels), and or encased in abiocompatible semi-permeable implant. In addition, the soluble TNFR maybe conjugated with polyethylene glycol (pegylated) to prolong its serumhalf-life or to enhance protein delivery.

In accord with this invention, medical disorders characterized byabnormal or excess expression of TNFα are administered a therapeuticallyeffective amount of a TNFα inhibitor. The TNFα inhibitor may be aTNFα-binding soluble TNFα receptor, preferably TNFR:Fc. As used herein,the phrase “administering a therapeutically effective amount” of atherapeutic agent means that the patient is treated with the agent in anamount and for a time sufficient to induce a sustained improvement in atleast one indicator that reflects the severity of the disorder. Animprovement is considered “sustained” if the patient exhibits theimprovement on at least two occasions separated by one or more weeks.The degree of improvement is determined based on signs or symptoms, anddeterminations may also employ questionnaires that are administered tothe patient, such as quality-of-life questionnaires.

Various indicators that reflect the extent of the patient's illness maybe assessed for determining whether the amount and time of the treatmentis sufficient. The baseline value for the chosen indicator or indicatorsis established by examination of the patient prior to administration ofthe first dose of the etanercept or other TNFα inhibitor. Preferably,the baseline examination is done within about 60 days of administeringthe first dose. If the TNFα antagonist is being administered to treatacute symptoms, such as for example to treat a traumatic knee injury,the first dose is administered as soon as practically possible after theinjury has occurred.

Improvement is induced by administering TNFR:Fc or other TNFα antagonistuntil the patient manifests an improvement over baseline for the chosenindicator or indicators. In treating chronic conditions, this degree ofimprovement is obtained by repeatedly administering this medicament overa period of at least a month or more, e.g., for one, two, or threemonths or longer, or indefinitely. A period of one to six weeks, or evena single dose, often is sufficient for treating acute conditions. Forinjuries or acute conditions, a single dose may be sufficient.

Although the extent of the patient's illness after treatment may appearimproved according to one or more indicators, treatment may be continuedindefinitely at the same level or at a reduced dose or frequency. Oncetreatment has been reduced or discontinued, it later may be resumed atthe original level if symptoms should reappear.

Any efficacious route of administration may be used to therapeuticallyadminister

TNFR:Fc or other TNFα antagonists. If injected, TNFR:Fc can beadministered, for example, via intra-articular, intravenous,intramuscular, intralesional, intraperitoneal or subcutaneous routes bybolus injection or by continuous infusion. Other suitable means ofadministration include sustained release from implants, aerosolinhalation, eyedrops, oral preparations, including pills, syrups,lozenges or chewing gum, and topical preparations such as lotions, gels,sprays, ointments or other suitable techniques. Alternatively,proteinaceous TNFα inhibitors, such as a soluble TNFR, may beadministered by implanting cultured cells that express the protein, forexample, by implanting cells that express TNFR:Fc. In one embodiment,the patient's own cells are induced to produce TNFR:Fc by transfectionin vivo or ex vivo with a DNA that encodes TNFR:Fc. This DNA can beintroduced into the patient's cells, for example, by injecting naked DNAor liposome-encapsulated DNA that encodes TNFR:Fc, or by other means oftransfection. When TNFR:Fc is administered in combination with one ormore other biologically active compounds, these may be administered bythe same or by different routes, and may be administered simultaneously,separately or sequentially.

TNFR:Fc or other soluble TNFRs preferably are administered in the formof a physiologically acceptable composition comprising purifiedrecombinant protein in conjunction with physiologically acceptablecarriers, excipients or diluents. Such carriers are nontoxic torecipients at the dosages and concentrations employed. Ordinarily, thepreparation of such compositions entails combining the TNFα antagonistwith buffers, antioxidants such as ascorbic acid, low molecular weightpolypeptides (such as those having fewer than 10 amino acids), proteins,amino acids, carbohydrates such as glucose, sucrose or dextrins,chelating agents such as EDTA, glutathione and other stabilizers andexcipients. Neutral buffered saline or saline mixed with conspecificserum albumin are exemplary appropriate diluents. In accordance withappropriate industry standards, preservatives may also be added, such asbenzyl alcohol. TNFR:Fc preferably is formulated as a lyophilizate usingappropriate excipient solutions (e.g., sucrose) as diluents. Appropriatedosages can be determined in standard dosing trials, and may varyaccording to the chosen route of administration. The amount andfrequency of administration will depend, of course, on such factors asthe nature and severity of the indication being treated, the desiredresponse, the age and condition of the patient, and so forth.

In one embodiment of the invention, TNFR:Fc is administered one time perweek to treat the various medical disorders disclosed herein, in anotherembodiment is administered at least two times per week, and in anotherembodiment is administered at least three times per week. An adultpatient is a person who is 18 years of age or older. If injected, theeffective amount of TNFR:Fc per adult dose ranges from 1-20 mg/m², andpreferably is about 5-12 mg/m². Alternatively, a flat dose may beadministered, whose amount may range from 5-100 mg/dose. Exemplary doseranges for a flat dose to be administered by subcutaneous injection are5-25 mg/dose, 25-50 mg/dose and 50-100 mg/dose. In one embodiment of theinvention, the various indications described below are treated byadministering a preparation acceptable for injection containing TNFR:Fcat 25 mg/dose, or alternatively, containing 50 mg per dose. The 25 mg or50 mg dose may be administered repeatedly, particularly for chronicconditions. If a route of administration other than injection is used,the dose is appropriately adjusted in accord with standard medicalpractices. In many instances, an improvement in a patient's conditionwill be obtained by injecting a dose of about 25 mg of TNFR:Fc one tothree times per week over a period of at least three weeks, or a dose of50 mg of TNFR:Fc one or two times per week for at least three weeks,though treatment for longer periods may be necessary to induce thedesired degree of improvement. For incurable chronic conditions, theregimen may be continued indefinitely, with adjustments being made todose and frequency if such are deemed necessary by the patient'sphysician.

For pediatric patients (age 4-17), a suitable regimen involves thesubcutaneous injection of 0.4 mg/kg, up to a maximum dose of 25 mg ofTNFR:Fc, administered by subcutaneous injection one or more times perweek.

The invention further includes the administration of TNFR:Fcconcurrently with one or more other drugs that are administered to thesame patient in combination with the TNFR:Fc, each drug beingadministered according to a regimen suitable for that medicament.“Concurrent administration” encompasses simultaneous or sequentialtreatment with the components of the combination, as well as regimens inwhich the drugs are alternated, or wherein one component is administeredlong-term and the other(s) are administered intermittently. Componentsmay be administered in the same or in separate compositions, and by thesame or different routes of administration. Examples of drugs to beadministered concurrently include but are not limited to antivirals,antibiotics, analgesics, corticosteroids, antagonists of inflammatorycytokines, DMARDs and non-steroidal anti-inflammatories. DMARDs that canbe administered in combination with the subject TNFα inhibitors such asTNFR:Fc include azathioprine, cyclophosphamide, cyclosporine,hydroxychloroquine sulfate, methotrexate, leflunomide, minocycline,penicillamine, sulfasalazine and gold compounds such as oral gold, goldsodium thiomalate and aurothioglucose. Additionally, TNFR:Fc may becombined with a second TNFα antagonist, including an antibody againstTNFα or TNFR, a TNFα-derived peptide that acts as a competitiveinhibitor of TNFα (such as those described in U.S. Pat. No. 5,795,859),a TNFR-IgG fusion protein other than etanercept, such as one containingthe extracellular portion of the p55 TNFα receptor, a soluble TNFR otherthan an IgG fusion protein, or other molecules that reduce endogenousTNFα levels, such as inhibitors of the TNFα converting enzyme (see e.g.,U.S. Pat. No. 5,594,106). In further embodiments of this invention,TNFR:Fc is administered in combination with pentoxifylline orthalidomide.

If an antibody against TNFα is used as the TNFα inhibitor, a preferreddose range is 0.1 to 20 mg/kg, and more preferably is 1-10 mg/kg.Another preferred dose range for anti-TNFα antibody is 0.75 to 7.5 mg/kgof body weight. Humanized antibodies are preferred, that is, antibodiesin which only the antigen-binding portion of the antibody molecule isderived from a non-human source. such antibodies may be injected oradministered intravenously.

In one preferred embodiment of the invention, the various medicaldisorders disclosed herein as being treatable with inhibitors such asTNFR:Fc are treated in combination with another cytokine or cytokineinhibitor. For example, TNFR:Fc may be administered in a compositionthat also contains a compound that inhibits the interaction of otherinflammatory cytokines with their receptors. Examples of cytokineinhibitors used in combination with TNFR:Fc include, for example,antagonists of TGFβ, Il-6 or Il-8. TNFα inhibitors such as TNFR:Fc alsomay be administered in combination with the cytokines GM-CSF, IL-2 andinhibitors of protein kinase A type 1 to enhance T cell proliferation inHIV-infected patients who are receiving anti-retroviral therapy. Othercombinations for treating the hereindescribed diseases include TNFR:Fcadministered concurrently with compounds that block the binding of RANKand RANK-ligand, such as antagonistic antibodies against RANK orRANK-ligand, soluble forms of RANK-ligand that do not trigger RANK,osteoprotegerin or soluble forms of RANK, including RANK:Fc. Solubleforms of RANK suitable for these combinations are described, forexample, in U.S. Pat. No. 6,017,729. The concurrent administration ofTNFR:Fc and RANK:Fc or TNFR:Fc and osteoprotegerin is useful forpreventing bone destruction in various settings including but notlimited to various rheumatic disorders, osteoporosis, multiple myelomaor other malignancies that cause bone degeneration, or anti-tumortherapy aimed at preventing metastasis to bone, or bone destructionassociated with prosthesis wear debris or with periodontitis.

The present invention also relates to the use of the disclosed TNFαinhibitors, such as TNFR:Fc, in the manufacture of a medicament for theprevention or therapeutic treatment of each medical disorder disclosedherein.

The disclosed TNFα inhibitors, compositions and combination therapiesdescribed herein are useful in medicines for treating bacterial, viralor protozoal infections, and complications resulting therefrom. One suchdisease is Mycoplasma pneumonia. In addition, provided herein is the useof TNFR:Fc to treat AIDS and related conditions, such as AIDS dementiacomplex, AIDS associated wasting, lipidistrophy due to antiretroviraltherapy; and Kaposi's sarcoma. Provided herein is the use of TNFR:Fc fortreating protozoal diseases, including malaria and schistosomiasis.Additionally provided is the use of TNFR:Fc to treat erythema nodosumleprosum; bacterial or viral meningitis; tuberculosis, includingpulmonary tuberculosis; and pneumonitis secondary to a bacterial orviral infection. Provided also herein is the use of TNFR:Fc to preparemedicaments for treating louse-borne relapsing fevers, such as thatcaused by Borrelia recurrentis. TNFR:Fc can also be used to prepare amedicament for treating conditions caused by Herpes viruses, such asherpetic stromal keratitis, corneal lesions, and virus-induced cornealdisorders. In addition, TNFR:Fc can be used in treating humanpapillomavirus infections. TNFR:Fc is used also to prepare medicamentsto treat influenza.

Cardiovascular disorders are treatable with the disclosed TNFαinhibitors, pharmaceutical compositions or combination therapies,including aortic aneurisms; arteritis; vascular occlusion, includingcerebral artery occlusion; complications of coronary by-pass surgery;ischemia/reperfusion injury; heart disease, including atheroscleroticheart disease, myocarditis, including chronic autoimmune myocarditis andviral myocarditis; heart failure, including chronic heart failure (CHF),cachexia of heart failure; myocardial infarction; restenosis after heartsurgery; silent myocardial ischemia; post-implantation complications ofleft ventricular assist devices; Raynaud's phenomena; thrombophlebitis;vasculitis, including Kawasaki's vasculitis; giant cell arteritis,Wegener's granulomatosis; and Schoenlein-Henoch purpura.

TNFα and IL-8 have been implicated as chemotactic factors inathersclerotic abdominal aortic aneurism (Szekanecz et al., Pathobiol62:134-139 (1994)). Abdominal aortic aneurism may be treated in humanpatients by administering a soluble TNFR, such as TNFR:Fc, which may beadministered in combination with an inhibitor of IL-8, such treatmenthaving the effect of reducing the pathological neovascularizationassociated with this condition.

A combination of a TNFα inhibitor and one or more otheranti-angiogenesis factors may be used to treat solid tumors, therebyreducing the vascularization that nourishes the tumor tissue. Suitableanti-angiogenic factors for such combination therapies include IL-8inhibitors, angiostatin, endostatin, kringle 5, inhibitors of vascularendothelial growth factor (such as antibodies against vascularendothelial growth factor), angiopoietin-2 or other antagonists ofangiopoietin-1, antagonists of platelet-activating factor andantagonists of basic fibroblast growth factor

In addition, the subject TNFα inhibitors, compositions and combinationtherapies are used to treat chronic pain conditions, such as chronicpelvic pain, including chronic prostatitis/pelvic pain syndrome. As afurther example, TNFR:Fc and the compositions and combination therapiesof the invention are used to treat post-herpetic pain.

Provided also are methods for using TNFα inhibitors, compositions orcombination therapies to treat various disorders of the endocrinesystem. For example, the TNFα inhibitors are used to treat juvenileonset diabetes (includes autoimmune and insulin-dependent types ofdiabetes) and also to treat maturity onset diabetes (includesnon-insulin dependent and obesity-mediated diabetes). In addition, thesubject compounds, compositions and combination therapies are used totreat secondary conditions associated with diabetes, such as diabeticretinopathy, kidney transplant rejection in diabetic patients,obesity-mediated insulin resistance, and renal failure, which itself maybe associated with proteinurea and hypertension. Other endocrinedisorders also are treatable with these compounds, compositions orcombination therapies, including polycystic ovarian disease, X-linkedadrenoleukodystrophy, hypothyroidism and thyroiditis, includingHashimoto's thyroiditis (i.e., autoimmune thyroiditis).

Conditions of the gastrointestinal system also are treatable with TNFαinhibitors, compositions or combination therapies, including coeliacdisease. In addition, the compounds, compositions and combinationtherapies of the invention are used to treat Crohn's disease; ulcerativecolitis; idiopathic gastroparesis; pancreatitis, including chronicpancreatitis and lung injury associated with acute pancreatitis; andulcers, including gastric and duodenal ulcers.

Included also are methods for using the subject TNFα inhibitors,compositions or combination therapies for treating disorders of thegenitourinary system, such as glomerulonephritis, including autoimmuneglomerulonephritis, glomerulonephritis due to exposure to toxins orglomerulonephritis secondary to infections with haemolytic streptococcior other infectious agents. Also treatable with the compounds,compositions and combination therapies of the invention are uremicsyndrome and its clinical complications (for example, renal failure,anemia, and hypertrophic cardiomyopathy), including uremic syndromeassociated with exposure to environmental toxins, drugs or other causes.Further conditions treatable with the compounds, compositions andcombination therapies of the invention are complications ofhemodialysis; prostate conditions, including benign prostatichypertrophy, nonbacterial prostatitis and chronic prostatitis; andcomplications of hemodialysis.

Also provided herein are methods for using TNFα inhibitors, compositionsor combination therapies to treat various hematologic and oncologicdisorders. For example, TNFR:Fc is used to treat various forms ofcancer, including acute myelogenous leukemia, Epstein-Barrvirus-positive nasopharyngeal carcinoma, glioma, colon, stomach,prostate, renal cell, cervical and ovarian cancers, lung cancer (SCLCand NSCLC), including cancer-associated cachexia, fatigue, asthenia,paraneoplastic syndrome of cachexia and hypercalcemia. Additionaldiseases treatable with the subject TNFα inhibitors, compositions orcombination therapies are solid tumors, including sarcoma, osteosarcoma,and carcinoma, such as adenocarcinoma (for example, breast cancer) andsquamous cell carcinoma. In addition, the subject compounds,compositions or combination therapies are useful for treating leukemia,including acute myelogenous leukemia, chronic or acute lymphoblasticleukemia and hairy cell leukemia. Other malignancies with invasivemetastatic potential can be treated with the subject compounds,compositions and combination therapies, including multiple myeloma. Inaddition, the disclosed TNFα inhibitors, compositions and combinationtherapies can be used to treat anemias and hematologic disorders,including anemia of chronic disease, aplastic anemia, includingFanconi's aplastic anemia; idiopathic thrombocytopenic purpura (ITP);myelodysplastic syndromes (including refractory anemia, refractoryanemia with ringed sideroblasts, refractory anemia with excess blasts,refractory anemia with excess blasts in transformation);myelofibrosis/myeloid metaplasia; and sickle cell vasocclusive crisis.

Various lymphoproliferative disorders also are treatable with thedisclosed TNFαinhibitors, compositions or combination therapies. Theseinclude, but are not limited to autoimmune lymphoproliferative syndrome(ALPS), chronic lymphoblastic leukemia, hairy cell leukemia, chroniclymphatic leukemia, peripheral T-cell lymphoma, small lymphocyticlymphoma, mantle cell lymphoma, follicular lymphoma, Burkitt's lymphoma,Epstein-Barr virus-positive T cell lymphoma, histiocytic lymphoma,Hodgkin's disease, diffuse aggressive lymphoma, acute lymphaticleukemias, T gamma lymphoproliferative disease, cutaneous B celllymphoma, cutaneous T cell lymphoma (i.e., mycosis fungoides) and Sézarysyndrome.

In addition, the subject TNFα inhibitors, compositions and combinationtherapies are used to treat hereditary conditions such as Gaucher'sdisease, Huntington's disease, linear IgA disease, and musculardystrophy.

Other conditions treatable by the disclosed TNFα inhibitors,compositions and combination therapies include those resulting frominjuries to the head or spinal cord, and including subdural hematoma dueto trauma to the head.

The disclosed TNFα inhibitors, compositions and combination therapiesare further used to treat conditions of the liver such as hepatitis,including acute alcoholic hepatitis, acute drug-induced or viralhepatitis, hepatitis A, B and C, sclerosing cholangitis and inflammationof the liver due to unknown causes.

In addition, the disclosed TNFα inhibitors, compositions and combinationtherapies are used to treat various disorders that involve hearing lossand that are associated with abnormal TNFα expression. One of these isinner ear or cochlear nerve-associated hearing loss that is thought toresult from an autoimmune process, i.e., autoimmune hearing loss. Thiscondition currently is treated with steroids, methotrexate and/orcyclophosphamide, which may be administered concurrently with theTNFR:Fc or other TNFα inhibitor. Also treatable with the disclosed TNFαinhibitors, compositions and combination therapies is cholesteatoma, amiddle ear disorder often associated with hearing loss.

In addition, the subject invention provides TNFα inhibitors,compositions and combination therapies for the treatment ofnon-arthritic medical conditions of the bones and joints. Thisencompasses osteoclast disorders that lead to bone loss, such as but notlimited to osteoporosis, including post-menopausal osteoporosis,periodontitis resulting in tooth loosening or loss, and prosthesisloosening after joint replacement (generally associated with aninflammatory response to wear debris). This latter condition also iscalled “orthopedic implant osteolysis.” Another condition treatable byadministering TNFRα inhibitors, such as TNFR:Fc, is temporal mandibularjoint dysfunction (TMJ).

A number of pulmonary disorders also can be treated with the disclosedTNFαinhibitors, compositions and combination therapies. One suchcondition is adult respiratory distress syndrome (ARDS), which isassociated with elevated TNFα, and may be triggered by a variety ofcauses, including exposure to toxic chemicals, pancreatitis, trauma orother causes. The disclosed compounds, compositions and combinationtherapies of the invention also are useful for treatingbroncho-pulmonary dysplasia (BPD); lymphangioleiomyomatosis; and chronicfibrotic lung disease of preterm infants. In addition, the compounds,compositions and combination therapies of the invention are used totreat occupational lung diseases, including asbestosis, coal worker'spneumoconiosis, silicosis or similar conditions associated withlong-term exposure to fine particles. In other aspects of the invention,the disclosed compounds, compositions and combination therapies are usedto treat pulmonary disorders, including chronic obstructive pulmonarydisease (COPD) associated with chronic bronchitis or emphysema; fibroticlung diseases, such as cystic fibrosis, idiopathic pulmonary fibrosisand radiation-induced pulmonary fibrosis; pulmonary sarcoidosis; andallergies, including allergic rhinitis, contact dermatitis, atopicdermatitis and asthma.

Cystic fibrosis is an inherited condition characterized primarily by theaccumulation of thick mucus, predisposing the patient to chronic lunginfections and obstruction of the pancreas, which results inmalabsorption of nutrients and malnutrition. TNFR:Fc may be administeredto treat cystic fibrosis. If desired, treatment with TNFR:Fc may beadministered concurrently with corticosteroids, mucus-thinning agentssuch as inhaled recombinant deoxyribonuclease I (such as PULMOZYME®;Genentech, Inc.) or inhaled tobramycin (TOBI®; Pathogenesis, Inc.).TNFR:Fc also may be administered concurrently with corrective genetherapy, drugs that stimulate cystic fibrosis cells to secrete chlorideor other yet-to-be-discovered treatments. Sufficiency of treatment maybe assessed, for example, by observing a decrease in the number ofpathogenic organisms in sputum or lung lavage (such as Haemophilusinfluenzae, Stapholococcus aureus, and Pseudomonas aeruginosa), bymonitoring the patient for weight gain, by detecting an increase in lungcapacity or by any other convenient means.

TNFR:Fc or TNFR:Fc combined with the cytokine IFNγ-1b (such asACTIMMUNE®; InterMune Pharmaceuticals) may be used for treating cysticfibrosis or fibrotic lung diseases, such as idiopathic pulmonaryfibrosis, radiation-induced pulmonary fibrosis and bleomycin-inducedpulmonary fibrosis. In addition, this combination is useful for treatingother diseases characterized by organ fibrosis, including systemicsclerosis (also called “scleroderma”), which often involves fibrosis ofthe liver. For treating cystic fibrosis, TNFR:Fc and IFNγ-1b may becombined with PULMOZYME® or TOBI® or other treatments for cysticfibrosis.

TNFR:Fc alone or in combination with IFNγ-1b may be administeredtogether with other treatments presently used for treating fibrotic lungdisease. Such additional treatments include glucocorticoids,azathioprine, cyclophosphamide, penicillamine, colchisicine,supplemental oxygen and so forth. Patients with fibrotic lung disease,such as IPF, often present with nonproductive cough, progressivedyspnea, and show a restrictive ventilatory pattern in pulmonaryfunction tests. Chest radiographs reveal fibrotic accumulations in thepatient's lungs. When treating fibrotic lung disease in accord with thedisclosed methods, sufficiency of treatment may be detected by observinga decrease in the patient's coughing (when cough is present), or byusing standard lung function tests to detect improvements in total lungcapacity, vital capacity, residual lung volume or by administering aarterial blood gas determination measuring desaturation under exercisingconditions, and showing that the patient's lung function has improvedaccording to one or more of these measures. In addition, patientimprovement may be determined through chest radiography results showingthat the progression of fibrosis in the patient's lungs has becomearrested or reduced.

In addition, TNF inhibitors (including soluble TNFRs or antibodiesagainst TNFα or TNFR) are useful for treating organ fibrosis whenadministered in combination with relaxin, a hormone that down-regulatescollagen production thus inhibiting fibrosis, or when given incombination with agents that block the fibrogenic activity of TGF-β.Combination therapies using TNFR:Fc and recombinant human relaxin areuseful, for example, for treating systemic sclerosis or fibrotic lungdiseases, including cystic fibrosis, idiopathic pulmonary fibrosis,radiation-induced pulmonary fibrosis and bleomycin-induced pulmonaryfibrosis.

Other embodiments provide methods for using the disclosed TNFαinhibitors, compositions or combination therapies to treat a variety ofrheumatic disorders. These include: adult and juvenile rheumatoidarthritis; systemic lupus erythematosus; gout; osteoarthritis;polymyalgia rheumatica; seronegative spondylarthropathies, includingankylosing spondylitis; and Reiter's disease. The subject TNFαinhibitors, compositions and combination therapies are used also totreat psoriatic arthritis and chronic Lyme arthritis. Also treatablewith these compounds, compositions and combination therapies are Still'sdisease and uveitis associated with rheumatoid arthritis. In addition,the compounds, compositions and combination therapies of the inventionare used in treating disorders resulting in inflammation of thevoluntary muscle, including dermatomyositis and polymyositis. Moreover,the compounds, compositions ant combinations disclosed herein are usefulfor treating sporadic inclusion body myositis, as TNFα may play asignificant role in the progression of this muscle disease. In addition,the compounds, compositions and combinations disclosed herein are usedto treat multicentric reticulohistiocytosis, a disease in which jointdestruction and papular nodules of the face and hands are associatedwith excess production of proinflammatory cytokines by multinucleatedgiant cells.

For purposes of this invention, patients are defined as having psoriaticarthrisis (PsA) if they have one or more swollen joints or one or morepainful or tender joints, and also manifest at least one psoriaticlesion of the skin or nails. The psoriatic lesions may appear before orafter the onset of swollen or tender joints. It is understood that priorto treatment, manifestations of PsA may have persisted over time, e.g.,for several months or years, and may involve several joints. Accordingto one classification system (reviewed in Alonso et al., 1991), PsApatients can be categorized based on their arthritic symptoms into fiveclinical subgroups: 1) DIP; 2) mutilans arthritis; 3) symmetricalpolyarthritis; 4) oligoarticular arthritis; and 5) ankylosingspondylitis-like. The disclosed therapies, compounds and compositionsare suitable for treating all five forms of PsA.

The TNFα inhibitors, compositions and combination therapies of theinvention may be used to inhibit hypertrophic scarring, a phenomenonbelieved to result in part from excessive TNFα secretion. TNF inhibitorsmay be administered alone or concurrently with other agents that inhibithypertrophic scarring, such as inhibitors of TGF-α.

Cervicogenic headache is a common form of headache arising fromdysfunction in the neck area, and which is associated with elevatedlevels of TNFα, which are believed to mediate an inflammatory conditionthat contributes to the patient's discomfort (Martelletti, Clin ExpRheumatol 18(2 Suppl 19):S33-8 (March-April, 2000)). Cervicogenicheadache may be treated by administering an inhibitor of TNFα asdisclosed herein, thereby reducing the inflammatory response andassociated headache pain.

The TNFα inhibitors, compositions and combination therapies of theinvention are useful for treating primary amyloidosis. In addition, thesecondary amyloidosis that is characteristic of various conditions alsoare treatable with TNFα inhibitors such as TNFR:Fc, and the compositionsand combination therapies described herein. Such conditions include:Alzheimer's disease, secondary reactive amyloidosis; Down's syndrome;and dialysis-associated amyloidosis. Also treatable with the compounds,compositions and combination therapies of the invention are inheritedperiodic fever syndromes, including familial Mediterranean fever,hyperimmunoglobulin D and periodic fever syndrome and TNF-receptorassociated periodic syndromes (TRAPS).

Disorders associated with transplantation also are treatable with thedisclosed TNFα inhibitors, compositions or combination therapies, suchas graft-versus-host disease, and complications resulting from solidorgan transplantation, including transplantion of heart, liver, lung,skin, kidney or other organs. TNFR:Fc may be administered, for example,to prevent or inhibit the development of bronchiolitis obliterans afterlung transplantation. Patients undergoing autologous hematopoietic stemcell transplantation in the form of peripheral blood stem celltransplantation may develop “engraftment syndrome,” or “ES,” which is anadverse and generally self-limited response that occurs about the timeof hematopoietic engraftment and which can result in pulmonarydeterioration. ES may be treated with inhibitors of either IL-8 or TNFα(such as TNFR:Fc), or with a combination of inhibitors against both ofthese cytokines

Ocular disorders also are treatable with the disclosed TNFα inhibitors,compositions or combination therapies, including rhegmatogenous retinaldetachment, and inflammatory eye disease, and inflammatory eye diseaseassociated with smoking and macular degeneration.

TNFα inhibitors such as TNFR:Fc and the disclosed compositions andcombination therapies also are useful for treating disorders that affectthe female reproductive system. Examples include, but are not limitedto, multiple implant failure/infertility; fetal loss syndrome or IVembryo loss (spontaneous abortion); preeclamptic pregnancies oreclampsia; and endometriosis.

In addition, the disclosed TNFα inhibitors, compositions and combinationtherapies are useful for treating obesity, including treatment to bringabout a decrease in leptin formation. Also, the compounds, compositionsand combination therapies of the invention are used to treat sciatica,symptoms of aging, severe drug reactions (for example, Il-2 toxicity orbleomycin-induced pneumopathy and fibrosis), or to suppress theinflammatory response prior, during or after the transfusion ofallogeneic red blood cells in cardiac or other surgery, or in treating atraumatic injury to a limb or joint, such as traumatic knee injury.Various other medical disorders treatable with the disclosed TNFαinhibitors, compositions and combination therapies include; multiplesclerosis; Behcet's syndrome; Sjogren's syndrome; autoimmune hemolyticanemia; beta thalassemia; amyotrophic lateral sclerosis (Lou Gehrig'sDisease); Parkinson's disease; and tenosynovitis of unknown cause, aswell as various autoimmune disorders or diseases associated withhereditary deficiencies.

The disclosed TNFα inhibitors, compositions and combination therapiesfurthermore are useful for treating acute polyneuropathy; anorexianervosa; Bell's palsy; chronic fatigue syndrome; transmissible dementia,including Creutzfeld-Jacob disease; demyelinating neuropathy;Guillain-Barre syndrome; vertebral disc disease; Gulf war syndrome;myasthenia gravis; silent cerebral ischemia; sleep disorders, includingnarcolepsy and sleep apnea; chronic neuronal degeneration; and stroke,including cerebral ischemic diseases.

Disorders involving the skin or mucous membranes also are treatableusing the disclosed TNFα inhibitors, compositions or combinationtherapies. Such disorders include acantholytic diseases, includingDarier's disease, keratosis follicularis and pemphigus vulgaris. Alsotreatable with the subject TNFα inhibitors, compositions and combinationtherapies are acne; acne rosacea; alopecia areata; aphthous stomatitis;bullous pemphigoid; burns; eczema; erythema, including erythemamultiforme and erythema multiforme bullosum (Stevens-Johnson syndrome);inflammatory skin disease; lichen planus; linear IgA bullous disease(chronic bullous dermatosis of childhood); loss of skin elasticity;mucosal surface ulcers; neutrophilic dermatitis (Sweet's syndrome);pityriasis rubra pilaris; psoriasis; pyoderma gangrenosum; and toxicepidermal necrolysis.

Patients are defined as having ordinary psoriasis if they lack the moreserious symptoms of PsA (e.g., distal interphalangeal joint DIPinvolvement, enthesopathy, spondylitis and dactylitis) but have one ofthe following: 1) inflamed swollen skin lesions covered with silverywhite scale (plaque psoriasis or psoriasis vulgaris); 2) small red dotsappearing on the trunk, arms or legs (guttate psoriasis); 3) smoothinflamed lesions without scaling in the flexural surfaces of the skin(inverse psoriasis); 4) widespread reddening and exfoliation of finescales, with or without itching and swelling (erythrodermic psoriasis);5) blister-like lesions (pustular psoriasis); 6) elevated inflamed scalplesions covered by silvery white scales (scalp psoriasis); 7) pittedfingernails, with or without yellowish discoloration, crumbling nails,or inflammation and detachment of the nail from the nail bed (nailpsoriasis).

Ordinary psoriasis may be treated by administering to a human patientcompositions containing a therapeutically effective amount of a TNFαinhibitor such as a soluble TNF receptor or an antibody against TNFα.

In one preferred embodiment, the therapeutic agent is a soluble TNFreceptor, and preferably is a TNFR-Ig. In a preferred embodiment, theTNFR-Ig is TNFR:Fc, which may be administered in the form of apharmaceutically acceptable composition as described herein. Psoriasismay be treated by administering TNFR:Fc one or more times per week bysubcutaneous injection, although other routes of administration may beused if desired. In one exemplary regimen for treating adult humanpatients, 25 mg of TNFR:Fc is administered by subcutaneous injection twotimes per week or three times per week for one or more weeks, andpreferably for four or more weeks. Alternatively, a dose of 5-12 mg/m²or a flat dose of 50 mg is injected subcutaneously one time or two timesper week for one or more weeks. In other embodiments, psoriasis istreated with TNFR:Fc in a sustained-release form, such as TNFR:Fc thatis encapsulated in a biocompatible polymer, TNFR:Fc that is admixed witha biocompatible polymer (such as topically applied hydrogels), andTNFR:Fc that is encased in a semi-permeable implant.

Various other medicaments used to treat ordinary psoriasis may also beadministered concurrently with compositions comprising TNFα inhibitors,such as TNFR:Fc. Such medicaments include: NSAIDs; DMARDs; analgesics;topical steroids; systemic steroids (e.g., prednisone); cytokines;antagonists of inflammatory cytokines; antibodies against T cell surfaceproteins; anthralin; coal tar; vitamin D3 and its analogs; topicalretinoids; oral retinoids; salicylic acid; and hydroxyurea. Suitableanalgesics for such combinations include: acetaminophen, codeine,propoxyphene napsylate, oxycodone hydrochloride, hydrocodone bitartrateand tramadol. DMARDs suitable for such combinations include:azathioprine, cyclophosphamide, cyclosporine, hydroxychloroquinesulfate, methotrexate, leflunomide, minocycline, penicillamine,sulfasalazine, oral gold, gold sodium thiomalate and aurothioglucose. Inaddition, the TNFR:Fc or other TNFR mimic may be administered incombination with antimalarials or colchicine. NSAIDs suitable for thesubject combination treatments of psoriasis include: salicylic acid(aspirin) and salicylate derivatives; ibuprofen; indomethacin;celecoxib; rofecoxib; ketorolac; nambumetone; piroxicam; naproxen;oxaprozin; sulindac; ketoprofen; diclofenac; and other COX-1 and COX-2inhibitors, propionic acid derivatives, acetic acid derivatives, fumaricacid derivatives, carboxylic acid derivatives, butyric acid derivatives,oxicams, pyrazoles and pyrazolones, including newly developedanti-inflammatories.

If an antagonist against an inflammatory cytokine is administeredconcurrently with TNFR:Fc to treat psoriasis, suitable targets for suchantagonists include TGFβ, Il-6 and Il-8.

In addition, TNFR:Fc may be used to treat psoriasis in combination withtopical steroids, systemic steroids, antagonists of inflammatorycytokines, antibodies against T cell surface proteins, anthralin, coaltar, vitamin D3 and its analogs (including 1,25-dihydroxy vitamin D3 andcalcipotriene), topical retinoids, oral retinoids (including but notlimited to etretinate, acitretin and isotretinoin), topical salicylicacid, methotrexate, cyclosporine, hydroxyurea and sulfasalazine. Inaddition, TNFR:Fc may be administered to treat psoriasis in combinationwith one or more of the following compounds; minocycline; misoprostol;oral collagen; 6-mercaptopurine; nitrogen mustard; gabapentin;bromocriptine; somatostatin; peptide T; anti-CD4 monoclonal antibody;fumaric acid; polyunsaturated ethyl ester lipids; zinc; and other drugsthat may be used to treat psoriasis. TNFR:Fc may also be used to treatpsoriasis in combination with the use of various oils, including fishoils, nut oils and vegetable oils; aloe vera; jojoba; Dead Sea salts;capsaicin; milk thistle; witch hazel; moisturizers; and Epsom salts. Inaddition, psoriasis may be treated with compositions containing TNFR:Fcin combination with the following therapies: plasmapheresis;phototherapy with ultraviolet light B; psoralen combined withultraviolet light A (PUVA); and sunbathing.

For determining the sufficiency of treatment when treating ordinarypsoriasis in accord with the invention, the TNFR:Fc (or other TNFαinhibitor) is administered in an amount and for a time sufficient toinduce an improvement in an indicator such as psoriasis area andseverity index (PASI) or an improvement in Target Lesion Assessmentscore, which is an index for assessing the severity of individual skinlesions. In one embodiment, the treatment is regarded as sufficient whenthe patient exhibits an at least 50% improvement in his or her PASIscore, and in another embodiment, when the patient exhibits an at least75% improvement in PASI score. The sufficiency of treatment forpsoriasis may also be determined by evaluating individual psoriaticlesions for improvement in severity (Psoriasis Target Lesion AssessmentScore), and continuing treatment until an improvement is noted accordingto this scoring system. This scoring system involves determining for anindividual lesion whether improvement has occurred in plaque elevation,amount and degree of scaling or degree of erythema, and target lesionresponse to treatment, each of which is separately scored. PsoriasisTarget Lesion Assessment Score is determined by adding together theseparate scores for all four of the aforementioned indicia.

In addition to human patients, inhibitors of TNFα are useful in thetreatment of autoimmune and inflammatory conditions in non-humananimals, such as pets (dogs, cats, birds, primates, etc.), domestic farmanimals (horses cattle, sheep, pigs, birds, etc.), or any animal thatsuffers from a TNFα-mediated inflammatory or arthritic condition. Insuch instances, an appropriate dose may be determined according to theanimal's body weight. For example, a dose of 0.2-1 mg/kg may be used.Alternatively, the dose is determined according to the animal's surfacearea, an exemplary dose ranging from 0.1-20 mg/m², or more preferably,from 5-12 mg/m². For small animals, such as dogs or cats, a suitabledose is 0.4 mg/kg. In a preferred embodiment, TNFR:Fc (preferablyconstructed from genes derived from the same species as the patient), oranother soluble TNFR mimic, is administered by injection or othersuitable route one or more times per week until the animal's conditionis improved, or it may be administered indefinitely.

EXAMPLE

Evaluation of TNFR:Fc in Patients with Psoriatic Arthritis.

Sixty patients with active psoriatic arthritis (PsA) were enrolled in aPhase II double-blind randomized, placebo controlled study to determinewhether the subcutaneous biweekly administration of etanercept(recombinant TNFR:Fc) was safe in this patient population and whetherefficacy could be documented for both the arthritic and psoriaticaspects of this disease.

In this study, a flat dose of 25 mg of TNFR:Fc was injectedsubcutaneously two times a week. After 12 weeks, patients who completedthe study were eligible for continuation into a 24 week open-labelextension of the study, with assessments made at weeks 16, 36 and 30days post-study. All patients participating in the study extensionreceived etanercept, including those patients who had received placeboduring the blinded portion of the study.

In order to qualify for enrollment, subjects had to have at least one ofthe following forms of PsA: 1) DIP involvement; 2) polyarticulararthritis, absence of rheumatoid nodules and presence of psoriasis; 3)arthritis mutilans; 4) asymmetric peripheral arthritis; or 5) ankylosingspondylitis-like PsA. Subjects furthermore had to exhibit three or moreswollen joints and three or more tender or painful joints at the time ofenrollment, and to have exhibited an inadequate response to NSAIDtherapy. Subjects who were on other medications, including methotrexate,NSAIDs or oral corticosteroids were permitted to continue these othertreatments at the same dose so long as the investigator considered theseother treatments to inadequately control the patient's disease.Methotrexate was concurrently taken by 47% of the etanercept group, and47% of the placebo group, NSAIDs were concurrently taken by by 67% ofthe etanercept and 77% of the placebos and oral corticosteroids by 40%of the etanercept and 20% of the placebo patients. Pain medications,including acetaminophen, codeine, propoxyphene napsylate, oxycodonehydrochloride, hydrocodone bitartrate and tramadol, also were permittedduring the study, as well as the use of topical tar compounds.

To qualify as having PsA, patients had to have experienced at least onepsoriatic lesion of the skin or nails. Patients were evaluated atbaseline (day 1 of treatment) as follows: 1) complete joint assessment;2) psoriasis assessment; 3) duration of morning stiffness; 4) healthassessment (quality of life) questionnaire, visual analog scale(HAQ/VAS); 5) patient global assessment; 6) erythrocyte sedimentationrate (ESR, Westergren); 7) C-reactive protein (CRP); and 8) urinalysis.At weeks 4 and 8, patients were evaluated as follows: 1) complete jointassessment; 2) psoriasis assessment; 3) duration of morning stiffness;4) HAQ/VAS; 5) patient global assessment. At the end of 12 weeks,subjects were evaluated as follows: 1) complete joint assessment; 2)psoriasis assessment; 3) focused physical exam; 4) duration of morningstiffness; 5) HAQ/VAS; 6) patient global assessment; 6) hematologyprofile; 7) chemistry profile; 8) ESR; 9) CRP; 10) urinalysis; 11) serumtested for antibody to TNFR:Fc. Only those patients whose psoriasis wasstable and covered ≧3% of body area were evaluated for psoriasisresponse during this trial, although patients whose psoriasis wasinactive or covered less area were permitted to enroll.

A primary endpoint for clinical improvement or worsening of PsA was thePsoriatic Arthritis Response score, which is a composite score based onthe following four measures: 1) patient self-assessment; 2) physicianassessment; 3) joint pain or tenderness; 4) joint swelling. Both self-and physician assessments, i.e., overall assessment of disease status,were measured according to a five point Likert scale, in which a patientwas considered as “improved” if his or her score decreased by onecategory, or as “worse” if his or her score increased by one category.Joint pain or tenderness was measured on a 5-point scale, wherein 1=noneand 5=severe (withdrawal on examination). Joint swelling was evaluatedon a 4-point scale in which 1=none; 2=mild (detectable synovialthickening without loss of bony contour); 3=moderate (loss ofdistinctness of bony contours); and 4=severe (bulging synovialproliferation with cystic characteristics). For this last measure, adecrease in swelling of ≧30% was scored as an “improvement,” and anincrease in swelling of ≧30% was scored as a “worsening.” Patients wereclassified as “improved” under the Psoriatic Arthritis Response scoringsystem if they exhibited an improvement in at least two of the fourmeasures described above, provided that one of the improved areas wasjoint pain or joint tenderness, and where there was no worsening in anyof the four measures.

In addition, a secondary endpoint used for assessing psoriatic arthritiswas a modified version of the American College of RheumatologyPreliminary Definition of Improvement in Rheumatoid Arthritis (modifiedACR 20 response) (Felson et al., 1995). To qualify as “improved”according to this measure, a patient must have exhibited ≧20%improvement in both tender joint count (78 joints assessed) and swollenjoint count (76 joints assessed), and also must have shown animprovement in three of the following five: 1) subject pain assessment;2) subject global assessment; 3) physician global assessment; 4) subjectself-assessed disability; 5) acute-phase reactant (Westergreenerythrocyte sedimentation rate or C-reactive protein level). The jointcount was done by scoring several different aspects of tenderness, suchas pressure and joint manipulation on physical examination, wherein eachjoint was scored as “tender” or “nontender.” Similarly, each joint isscored after physical examination as “swollen” or “not swollen.” Thesubject's pain assessment was based on a horizontal visual analog scale(usually 10 cm) or Likert scale. The subject's and physician's globalassessments of the subject's current disease status was based on ananchored horizontal visual analog scale (usually 10 cm), or Likert scaleresponse. The subject's self-assessment of disability was based on anyof the following measures, all of which have been validated in RAtrials: Arthritis Impact Measurement Scale (AIMS); Health AssessmentQuestionnaire; the Quality (or Index) of Well Being Scale; the McMasterHealth Inventory Questionnaire (MHIQ); and the McMaster-TorontoArthritis patient preference questionnaire (MACTAR).

A primary endpoint used to assess the psoriatic aspects of PsA was thestandard psoriasis area and severity index (PASI) (Fredriksson andPetersson, Dermatologica 157:238-244, 1978). For this study, a positivetreatment response was defined as an at least 50% or an at least 75%improvement in a patient's PASI score. For assessing area and severity,the body is divided into four regions: head (10%); trunk (30%); upperextremities (20%); and lower extremities (40%). Each quadrant also wasscored for the severity of erythema (E), infiltration (I) anddesquamation (D), using a four point scale, in which 0=no symptomspresent; 1=slight symptoms; 2=moderate symptoms; 3=striking symptoms;4=exceptionally striking symptoms. Using a 6-point scale, each regionwas scored also for the percent of total area that was involved in thepsoriatic manifestations of the disease, wherein 0=no involvement;1=<10% involvement; 2=10−<30% involvement; 3=30−<50% involvement;4=50−<70% involvement; 5=70−<90% involvement; 6=90-100% involvement.PASI scores were calculated according to the formula given below, inwhich E=severity score for erythrema, I=severity score for infiltration,D=severity score for desquamation and A=total area involved. In thisformula, the letters “h,” “t,” “u” and “l” represent, respectively, thescores in each of the four body regions, i.e., head, trunk, upperextremities and lower extremities. The PASI score varies in steps of 0.1units from 0.0 (no psoriatic lesions at all) to 72.0 (completeerythroderma of the severest possible degree).

PASI=0.1(Eh+Ih+Dh)Ah+0.3(Et+It+Dt)At+0.2(Eu+Iu+Du)Au+0.4(El+Il+Dl)Al

A secondary endpoint used for the psoriatic aspect of psoriaticarthritis was the Target Lesion Assessment Score. This score wasdetermined for a single target lesion that was selected to be monitoredthroughout the trial. This measurement is a composite of four differentevaluations: 1) plaque evaluation; 2) scaling; 3) erythrema; and 4)target lesion response to treatment. The following scale was used forthe plaque elevation: 0=none (no evidence of plaque above normal skinlevel); 1=mild (slight but definite elevation above normal skin level);2=moderate (moderate elevation with rounded or sloped edges to plaque);3=severe (hard, marked elevation with sharp edges to plaque); 4=verysevere (very marked elevation with very hard sharp edges to plaque). Forthe scaling assessment: 0=none (no scaling on the lesion); 1=mild(mainly fine scales, with some of the lesion at least partiallycovered); 2=moderate (somewhat coarser scales, most of the lesion atleast partially covered); 3=severe (coarse, thick scales, virtually allthe lesion covered, rough surface); 4=very severe (very coarse thickscales, all the lesions covered, very rough surface). For the erythemaevaluation: 0=none (no erythema); 1=mild (light red coloration);2=moderate (red coloration); 3=severe (very red coloration); 4=verysevere (extreme red coloration). For target lesion response to treatmentscore: 0=completely cleared; 1=almost cleared (˜90% improvement);2=marked response (˜75% improvement); 3=moderate response (˜50%improvement); 4=slight response (˜25% improvement); 5=conditionunchanged; 6=condition worsened. The patient's Target Lesion AssessmentScore was determined by summing the plaque, scaling, erythema and targetlesion response scores for the monitored lesion. If the monitored lesionworsened, the percentage change from baseline was recorded as a negativenumber.

Treatment and placebo groups were compared in accord with themeasurements described above, as well as for demographic and backgroundcharacteristics; premature discontinuation rate; pain medicationrequirements; toxicities; serious adverse events; side effects reportedby patients; number of weeks on drug until subjects met criteria forimprovement, and response according to PsA subtype. Results wereanalyzed using standard statistical methods.

Dosing Regimen

Recombinant human TNFR:Fc (etanercept) from Immunex Corporation was usedin this study. The gene fragments encoding the etanercept polypeptideswere expressed in a Chinese hamster ovary (CHO) expression vector.

TNFR:Fc was supplied as a sterile lyophilized powder containing 10 mg or25 mg TNFR:Fc; 40 mg mannitol, USP; 10 mg sucrose, NF; and 1.2 mgtromethamine (TRIS), USP per vial. Patients received either a dose of 25mg of etanercept or a placebo. Vials of etanercept oridentically-appearing placebo were reconstituted by aseptic injection of1.0 mL Bacteriostatic Water for Injection, USP, (containing 0.9% benzylalcohol), and was not filtered during preparation or prior toadministration. If storage was required, the reconstituted solutionswere stored at 2-8° C. (36-46° F.) in the original vial or in a plasticsyringe for a period of no longer than 28 days. Dose was not changedduring the study. Study drug was given twice weekly at approximately thesame time of day.

Results

Study drug was well tolerated in all patients, and adverse events wereconsistent with this population and were equally distributed among bothtreatment groups. As illustrated in Tables 1-4, etanercept induced asignificant improvement as compared with the placebo group in PsoriaticArthritis Response (Table 1), ACR20 (Table 2), ACR50 (Table 3), PASIscore, 50% improvement (Table 4), PASI score, 75% improvement (Table 5)and improvement in Target Lesion Assessment Score (Table 6). Thefractions shown in Tables 1-5 represent numbers of patients. Forexample, the first entry in Table 1, which is “4/30,” indicates that 4of 30 patients in the placebo group scored as “improved” according tothe Psoriatic Arthritis Response measurements. The tables includeP-values for the differences between the two study groups, the groupsbeing labeled as “PLACEBO” and “TNFR:Fc.” All of the tables include datacalculated after the first four weeks of the open label extensionportion of the study (“EXTENSION”), during which all of the patients inboth study groups received etanercept.

Table 1 shows the number of patients in each treatment group who scoredas “improved” according to the Psoriatic Arthritis Response scoringsystem described above. By four weeks, there was a highly significantdifference between etanercept and placebo groups. Moreover, after beingswitched to etanercept during the extension, those patients who hadreceived placebo during the blinded portion of the study were seen toexhibit an improvement over baseline (Table 1, Placebo, EXTENSION).These results indicate that etanercept acts rapidly to alleviate manyaspects of psoriatic arthritis.

TABLE 1 Psoriatic Arthritis Response Placebo TNFR:Fc P-value  4 weeks 4/30 (13%) 23/30 (77%) 0.000  8 weeks  7/30 (23%) 25/30 (83%) 0.000 12weeks  6/30 (20%) 26/30 (87%) 0.000 EXTENSION 17/23 (74%) 21/25 (84%)0.356

Tables 2 and 3, respectively, illustrate the study results for the ACR20and ACR50 endpoints. For either measure, a significant differencebetween etanercept and placebo groups was observed at all three timepoints during the blinded portion of the study. Given the differencesbetween test and placebo groups after only four weeks of treatment(P=0.000 for ACR20 and P=0.011 for ACR50), these data suggest thatnotable improvement in ACR scores occurred within the etanercept groupvery soon after treatment was initiated, possibly after a single dose ofetanercept. During the 4 week extension period, during which all of thepatients received etanercept, a striking improvement in both ACR20 andACR50 was seen in those patients who had received placebo during thefirst 12 weeks (Tables 2 and 3).

TABLE 2 ACR20 Response Placebo TNFR:Fc P-value  4 weeks 1/30 (3%) 18/30(60%) 0.000  8 weeks  3/30 (10%) 19/30 (63%) 0.000 12 weeks  4/30 (13%)22/30 (73%) 0.000 EXTENSION 11/23 (48%) 18/25 (72%) 0.093

TABLE 3 ACR50 Response Placebo TNFR:Fc P-value  4 weeks 0/30 (0%)  6/30(20%) 0.011  8 weeks 1/30 (3%) 11/30 (37%) 0.001 12 weeks 1/30 (3%)15/30 (50%) 0.000 EXTENSION  7/23 (30%) 11/25 (44%) 0.316

The results of the psoriasis evaluations are presented in Tables 4-6.Tables 4 and 5, respectively, present the numbers and percentages ofpatients in each group who exhibited a 50% or 75% improvement in PASIscore, while Table 6 presents Target Lesion Assessment scores, theselatter being denoted as percent improvement over baseline. The data inTables 4-6 clearly indicate that etanercept induced an improvement inpsoriasis for a large percentage of the patients who received it. Whensingle lesions were evaluated (Table 6), the improvement in psoriasiswas even more apparent than when PASI scores were used (Tables 4 and 5).It is notable also that, for either PASI scores (Tables 4 and 5) orPsoriasis Target Lesion Assessment Score (Table 6), the scores of theplacebo group improved after these patients were switched to etanerceptduring the extension.

Though not shown in Table 6, Target Lesion Assessment Scores forpatients who were concurrently receiving methotrexate (14 of the 30patients in the etanercept group, and 14 patients in the placebo group)were compared with the scores of those patients who did not takemethotrexate. Little difference in this index was noted between thepatients who received methotrexate and those who did not receive it.

TABLE 4 PASI Score-50% Improvement Placebo TNFR:Fc P-value  4 weeks 0/19(0%) 4/19 (21%) 0.037  8 weeks 1/19 (5%) 7/19 (37%) 0.019 12 weeks  4/19(21%) 8/19 (42%) 0.165 EXTENSION  6/16 (38%) 6/15 (40%) 0.856

TABLE 5 PASI Response Rate 75% Improvement Placebo TNFR:Fc P-value  4weeks 0/19 (0%) 1/19 (5%)  0.264  8 weeks 0/19 (0%) 2/19 (11%) 0.153 12weeks 0/19 (0%) 4/19 (21%) 0.037 EXTENSION 1/16 (6%) 4/15 (27%) 0.113

TABLE 6 Psoriasis Target Lesion Assessment (Percent Improvement orWorsening Compared with Baseline) Placebo TNFR:Fc P-value  4 weeks Mean(SD) 2.7 (27.6) 21.2 (35.2) 0.120 Median 0.0 14.3 MIN--MAX −50.0 −50.0−33.3 −100.0 N 19 19  8 weeks Mean (SD) −7.5 (25.3) 28.5 (34.1) 0.003Median 0.0 29.2 MIN--MAX −50.0 −20.0 −33.3 −100.0 N 17 18 12 weeks Mean(SD) 9.5 (23.2) 45.7 (31.6) 0.001 Median 0.0 50.0 MIN--MAX −25.0 −50.0−16.7 −100.0 N 16 19 EXTENSION Mean (SD) 28.9 (41.2) 47.1 (35.8) 0.263Median 36.7 50.0 MIN--MAX −100.0 −66.7 −33.3 −100.0 N 16 15

1. A method for treating a patient having psoriatic arthritis comprisingadministering to the patient a therapeutically effective dose ofTNFR:Fc.
 2. The method of claim 1, wherein the patient exhibitspsoriasis symptoms as well as psoriatic arthritis symptoms.
 3. Themethod of claim 2, wherein (a) a dose of 50 milligrams of TNFR:Fc isadministered twice per week for at least 2 months, and then (b) TNFR:Fcis administered at a reduced dose or at a reduced frequency.
 4. Themethod of claim 3, wherein the administration of (b) is at a dose ofeither 25 milligrams twice per week or 50 milligrams once per week. 5.The method of claim 1, wherein TNFR:Fc is administered by subcutaneousinjection.
 6. The method of claim 1, wherein the dose of TNFR:Fcadministered is either 50 mg once per week or 25 mg twice per week. 7.The method of claim 1, wherein methotrexate, leflunomide, orsulfasalazine is administered concurrently.
 8. The method of claim 1,wherein a nonsteroidal anti-inflammatory drug (NSAID) is administeredconcurrently.
 9. The method of claim 2, wherein methotrexate,leflunomide, sulfasalazine, or an NSAID is administered concurrently.10. The method of claim 1, wherein the patient scores as “improved”according to the Psoriatic Arthritis Response scoring system.
 11. Themethod of claim 1, wherein the patient achieves an ACR20 responseaccording to the modified version of the American College ofRheumatology Preliminary Definition of Improvement in RheumatoidArthritis.
 12. The method of claim 2, wherein the patient scores as“improved” according to the Psoriatic Arthritis Response scoring system.13. The method of claim 2, wherein the patient achieves an ACR20response according to the modified version of the American College ofRheumatology Preliminary Definition of Improvement in RheumatoidArthritis.
 14. The method of claim 2, wherein the patient achieves a 50%improvement in PASI score.
 15. A method for treating a patient havingpsoriatic arthritis comprising administering to the patient atherapeutically effective dose of TNFR:Fc by subcutaneous injection. 16.The method of claim 15, wherein the patient achieves an ACR20 responseaccording to the modified version of the American College ofRheumatology Preliminary Definition of Improvement in RheumatoidArthritis.
 17. The method of claim 15, wherein a nonsteroidalanti-inflammatory drug (NSAID) is administered concurrently.
 18. Themethod of claim 15, wherein methotrexate, leflunomide, or sulfasalazineis administered concurrently.
 19. The method of claim 15, wherein thedose of TNFR:Fc administered is either 50 mg once per week or 25 mgtwice per week.
 20. The method of claim 15, wherein the patient exhibitspsoriasis symptoms as well as psoriatic arthritis symptoms and thepatient achieves a 50% improvement in PASI score.